Submissions for variant NM_004360.5(CDH1):c.2072C>T (p.Ala691Val)

dbSNP: rs569086883

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190108	SCV001357524	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 691 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001863013	SCV002310637	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-10-16	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 927094). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 691 of the CDH1 protein (p.Ala691Val).
Ambry Genetics	RCV001190108	SCV002725701	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-15	criteria provided, single submitter	clinical testing	The p.A691V variant (also known as c.2072C>T), located in coding exon 13 of the CDH1 gene, results from a C to T substitution at nucleotide position 2072. The alanine at codon 691 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV004761963	SCV005370002	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631)